EAE TrainingPROTOCOL­SPECIFIC

EAE TrainingPROTOCOL­SPECIFIC

20092009

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ObjectivesObjectives

Definitions

Assessment of Adverse Events

EAE Reporting

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EAE Reporting Materials EAE Reporting Materials

EAE Manual

EAE Reporting Form

EAE Reporting FormCompletion Instructions

AE Grading Table

Protocol

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Expedited Adverse Event (EAE)Expedited Adverse Event (EAE)

An adverse event that meets the criteria for expedited reporting to Division of AIDS (DAIDS).

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Adverse EventAdverse Event

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

(ICH E2A)

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Serious Adverse Event (SAE)Serious Adverse Event (SAE)

A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose:

Results in death,

Is life-threatening,

Requires inpatient hospitalization or prolongation of existing hospitalization,

Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect.

In addition, “…important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above…should also usually be considered serious.”

(ICH E2A)   

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Adverse Event vs. Event OutcomeAdverse Event vs. Event Outcome

Death Death is an outcome and is not usually considered to be an AE.

• Example: If “death due to myocardial infarction” is reported, “myocardial infarction” can be selected and death should be captured as the outcome.

If the only information reported is death, then the most specific death term available should be selected.

• Example: If a reporter states only that “a study subject was found dead,” “found dead” can be selected.

• Example: If the autopsy report states, “the cause of death was natural”, “Death from natural causes” can be selected.

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Adverse Event vs. Event OutcomeAdverse Event vs. Event Outcome

Hospitalization

Hospitalization is a consequence and is not usually considered an AE.

• Example: If “hospitalization due to congestive heart failure” is reported, “congestive heart failure” can be selected and hospitalization should be captured as the consequence of the event.

If the only information reported is the outcome term, then the most specific term available should be selected.

• Example: If a reporter states only that “a study subject was hospitalized,” “hospitalization” can be selected.

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Hospitalization: Exemptions from expedited reportingHospitalization: Exemptions from expedited reporting

Hospitalization in the absence of a medical AE is not in itself an AE and does not need to be reported in an expedited time frame.

Admission unrelated to an AE (e.g. for labor/delivery, aging-related cosmetic surgery, administrative or social admission)

Protocol-specified admission (e.g. for procedure required by protocol)

Admission for diagnosis or treatment for pre-existing condition (unless it is worsening or increasing in frequency)• A new AIDS-defining event in HIV-infected subject would be

considered worsening of pre-existing condition of HIV infection

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SeveritySeverity

Describes the intensity of the event

Events are graded on a severity scale

Events are graded on a severity scale of 1-5:

• 1 = Mild

• 2 = Moderate

• 3 = Severe

• 4 = Potentially Life-threatening

• 5 = Death

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Grading Severity of EventsGrading Severity of Events

Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (Version 1.0) December 2004 (Clarification August 2009):

• Web Site: http://rcc.tech-res.com

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EXAMPLEEXAMPLE FROM THE DIVISION OF AIDS FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTSADULT AND PEDIATRIC ADVERSE EVENTS

EXAMPLEEXAMPLE FROM THE DIVISION OF AIDS FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTSADULT AND PEDIATRIC ADVERSE EVENTS

CLINICALCLINICALPARAMETER GRADE 1

MILD

GRADE 2MODERATE

GRADE 3SEVERE

GRADE 4POTENTIALLY

LIFE-THREATENING

ESTIMATING SEVERITY GRADE

Clinical adverse event NOT identified elsewhere in this DAIDS AE grading table

Symptoms causing no or minimal interference with usual social & functional activities

Symptoms causing greater than minimal interference with usual social & functional activities

Symptoms causing inability to perform usual social & functional activities

Symptoms causing inability to perform basic self-care functions OR Medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death

Death = Grade 5

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EXAMPLEEXAMPLE FROM THE DIVISION OF AIDS FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTSADULT AND PEDIATRIC ADVERSE EVENTS

EXAMPLEEXAMPLE FROM THE DIVISION OF AIDS FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTSADULT AND PEDIATRIC ADVERSE EVENTS

SYSTEMIC

PARAMETER GRADE 1MILD

GRADE 2MODERATE

GRADE 3SEVERE

GRADE 4POTENTIALLY

LIFE-THREATENING

Chills Symptoms causing no or minimal interference with usual social & functional activities

Symptoms causing greater than minimal interference with usual social & functional activities

Symptoms causing inability to perform usual social & functional activities

N/A

Fever (nonaxillary) 37.7 – 38.6C 38.7 – 39.3C 39.4 – 40.5C > 40.5C

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EXAMPLEEXAMPLE FROM THE DIVISION OF AIDS FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTSADULT AND PEDIATRIC ADVERSE EVENTS

EXAMPLEEXAMPLE FROM THE DIVISION OF AIDS FROM THE DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTSADULT AND PEDIATRIC ADVERSE EVENTS

PARAMETER GRADE 1MILD

GRADE 2MODERATE

GRADE 3SEVERE

GRADE 4POTENTIALLY

LIFE-THREATENING

INFECTIONInfection (any other than HIV infection)

Localized, no systemic antimicrobial treatment indicated AND

Symptoms causing no or minimal interference with usual social & functional activities

Systemic antimicrobial treatment indicated OR

Symptoms causing greater than minimal interference with usual social & functional activities

Systemic antimicrobial treatment indicated AND

Symptoms causing inability to perform usual social & functional activities OR

Operative intervention (other than simple incision and drainage) indicated

Life-threatening consequences

(e.g. septic shock)

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Severity vs. SeriousSeverity vs. Serious

Severity is not the same as Serious

Severity = Intensity

• e.g., chest pain, moderate severity

Serious (SAE) = Based on patient/event outcome or action criteria

• Used to define regulatory reporting obligations

AE classification: must divorce usage of serious in a clinical sense from serious in a regulatory sense

For clinical connotations, use severity descriptors

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Action Taken with DrugAction Taken with Drug

Action Taken with Drug:

• Withdrawn

• Dose reduced

• Dose increased

• Dose not changed

• Unknown

• Not applicable

ICH E2B (R3)

Action Taken with Drug:

• O: Course completed or Subject OFF study agent at AE

• C: Continued without change

• R: Dose or schedule reduced

• T: Temporarily held

• D: Permanently discontinued

• U: unknown

DAIDS EAE Form

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OutcomeOutcome

Outcome of reaction/event at the time of last observation • Recovered/resolved• Recovering/resolving• Not recovered/not resolved• Recovered/resolved with sequelae• Fatal• Unknown

Outcome of subject in study• Remains in Study• Withdrawn• Lost to follow-up• Death

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ExpectednessExpectedness

Pertains to whether an event is expected or unexpected (on the basis of previous observation, not what might be anticipated from the pharmacological properties of the product)

Unexpected: the nature or severity of the adverse event is not consistent with the applicable product information (e.g. Investigator’s Brochure for unapproved product, Package Insert for approved product)

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Relatedness (Causality)Relatedness (Causality)

No standard international nomenclature

Conveys that a “causal relationship” between the study product and the adverse event is “at least a reasonable possibility” [ICH E2A]

• Facts (evidence) exist to suggest the relationship

Judged by:

• Reporting health professional

• Sponsor

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Standard determinations include:

• Is there [Drug Exposure] and [Temporal Association]?

• Is there [Dechallenge/Rechallenge] or [Dose Adjustments]?

• Any known association per [Investigator’s Brochure] or [Package Insert]?

• Is there [Biological Plausibility]?

• Any other possible [Etiology]?

Determination of RelatednessDetermination of Relatedness

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RelatednessRelatedness

Judgment of a relationship between AE and study agent.

An event is assessed as:

• Definitely related…

• Probably related…

• Possibly related…

• Probably not related…

• Not related…

• Pending relationship…

…to the study agent

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Comprehensive, stand-alone “medical story”• Written in logical time sequence• Include key information from supplementary records• Include relevant autopsy or post-mortem findings

Summarize all relevant clinical and related information, including:• Study subject characteristics• Therapy details• Medical history• Clinical course of the event(s)• Diagnosis (workup, relevant tests/procedures, lab results)• Other information that supports or refutes an AE

> ICH E2D

NarrativeNarrative

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AssessmentAssessment

Study physician listed on the1572 / Investigator of Record (IoR) Agreement assesses the events:

• Seriousness

• Severity

• Relationship

• Expectedness(only applies to Targeted)

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Review and Assessment of EAE/SAEReview and Assessment of EAE/SAE

Assemble all information available and use medical judgment

Standard for each AE:

• Select [Seriousness Criteria]

• Grade [Severity] per DAIDS Toxicity Table

• Specify [Actions Taken on Study Product]

• Specify [Outcome of SAE/EAE]. If Outcome is not resolved at time of evaluation, follow until resolution or stability at each study visit

• Is it [Expected]?

• Is it [Related]?

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New vs. Follow-up reportsNew vs. Follow-up reports

New

A reportable event first occurs.

An ongoing event increases in severity to a higher grade than previously reported.

An event fully resolves to baseline status and then recurs at a reportable level.

Follow-up

DAIDS requests additional information.

Study physician changes assessment of relationship to study agent.

Additional significant information becomes available (e.g. autopsy report, death certificate).

Results of rechallenge.

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The protocol will specifyone level ofadverse event reporting:

• Standard

• Intensive

• Targeted

• Other: SAE (added 2008)

Levels of Expedited AdverseEvent ReportingLevels of Expedited AdverseEvent Reporting

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Standard Level

IntensiveLevel

Targeted Level

Deaths All All All

Disabilities/Incapacities All All All

Congenital anomalies,birth defects, fetal losses All All All

Hospitalization/Intervention SADRs SADRs

Unexpected SADRs

Life-threatening

Grade 4 SADRs Grade 4 SADRsUnexpected

Clinical SADRs

Other events Grade 3 SADRs

Levels of Expedited AdverseEvent Reporting - SummaryLevels of Expedited AdverseEvent Reporting - Summary

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EAE Reporting PeriodEAE Reporting Period

Entire study duration for an individual subject (from enrollment until study completion or discontinuation for that particular subject).

…or as specified in the protocol.

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EAE Reporting PeriodEAE Reporting Period

After the EAE Reporting Period, only the following should be reported:

• Unexpected, Serious, Clinical SADRs If the study staff becomes aware of their occurrence on a passive basis (i.e. through publicly available information, not active follow up)

– Example: Obituary in the newspaper

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EAE Study Physician signatureEAE Study Physician signature

Physician signature signifies physician review and sign off

The EAE report may be sent in without the study physician signature, if necessary.

BUT

The completed signature page must be submitted to the RCC Safety Office within 3 business days of submitting the original EAE.

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EAE Reporting TimeframeEAE Reporting Timeframe

Within 3 business days of site awareness that an event has occurred at a reportable level.

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Confirmation Of ReceiptConfirmation Of Receipt

The RCC Safety Office sends a confirmation email for all new reports.

It is the site’s responsibility to follow-up if they do not receive a confirmation email.

How to Report EAEsHow to Report EAEs

Reports must be submitted on theEAE form available on the RCC Web sitehttp://rcc.tech-res.com/.

DAERS: DAIDS AE Reporting System: web-based electronic submission https://daidses.niaid.nih.gov/Phoenix

• If reporting via DAERS, no paper form needed

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How to Report EAEsHow to Report EAEs

Reports may be submitted via FAX, E-mail or DAERS:

• FAX: 1-301-897-1710or 1-800-275-7619 (USA only)

• Email: RCCSafetyOffice@tech-res.com

• If e-mailing, scan or FAX signature page

• DAERS: https://daidses.niaid.nih.gov/Phoenix

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Where to Get HelpWhere to Get Help

RCC Safety Office:

• E-mail: RCCSafetyOffice@tech-res.com

• Telephone: 1-301-897-1709 or 1-800-537-9979 (US Only)

• Fax: 1-301-897-1710 or 1 -800-275-7619 (US Only)

DAERS help: DAIDS-ESSupport@niaid.nih.gov

• Phone: 240-499-2239 (outside US), 866-337-1605 (US)

• Fax: 301-948-2242 (outside US), 866-337-1606 (US)

• Live assistance is available from 8:30 am to 5:30 pm EST, Monday to Friday (Excluding US Holidays)

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Overview of Reporting TimelinesOverview of Reporting Timelines

Protocol­Specific InformationProtocol­Specific Information